title: Enhancement of antitumor immunity in lung cancer by targeting myeloid-derived suppressor cell pathways.
abstract: Chemoresistance due to heterogeneity of the tumor microenvironment (TME) hampers the long-term efficacy of first-line therapies for lung cancer. Current combination therapies for lung cancer provide only modest improvement in survival, implicating necessity for novel approaches that suppress malignant growth and stimulate long-term antitumor immunity. Oxidative stress in the TME promotes immunosuppression by tumor-infiltrating myeloid-derived suppressor cells (MDSC), which inhibit host protective antitumor immunity. Using a murine model of lung cancer, we demonstrate that a combination treatment with gemcitabine and a superoxide dismutase mimetic targets immunosuppressive MDSC in the TME and enhances the quantity and quality of both effector and memory CD8(+) T-cell responses. At the effector cell function level, the unique combination therapy targeting MDSC and redox signaling greatly enhanced cytolytic CD8(+) T-cell response and further decreased regulatory T cell infiltration. For long-term antitumor effects, this therapy altered the metabolism of memory cells with self-renewing phenotype and provided a preferential advantage for survival of memory subsets with long-term efficacy and persistence. Adoptive transfer of memory cells from this combination therapy prolonged survival of tumor-bearing recipients. Furthermore, the adoptively transferred memory cells responded to tumor rechallenge exerting long-term persistence. This approach offers a new paradigm to inhibit immunosuppression by direct targeting of MDSC function, to generate effector and persistent memory cells for tumor eradication, and to prevent lung cancer relapse.
authors.affiliation: Authors' Affiliations: Departments of Pathology, Medicine, Microbiology, and Pediatrics, The University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Anandi
authors.initials: A
authors.lastname: Sawant
authors.forename: Cara C
authors.initials: CC
authors.lastname: Schafer
authors.forename: Tong Huan
authors.initials: TH
authors.lastname: Jin
authors.forename: Jaroslaw
authors.initials: J
authors.lastname: Zmijewski
authors.forename: Hubert M
authors.initials: HM
authors.lastname: Tse
authors.forename: Justin
authors.initials: J
authors.lastname: Roth
authors.forename: Zhihuan
authors.initials: Z
authors.lastname: Sun
authors.forename: Gene P
authors.initials: GP
authors.lastname: Siegal
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Thannickal
authors.forename: Stefan C
authors.initials: SC
authors.lastname: Grant
authors.forename: Selvarangan
authors.initials: S
authors.lastname: Ponnazhagan
authors.forename: Jessy S
authors.initials: JS
authors.lastname: Deshane
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D018827:Carcinoma, Lewis Lung / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D003131:Combined Modality Therapy; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000627:therapeutic use; D005260:Female; D007108:Immune Tolerance / Q000276:immunology*; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D016219:Immunotherapy, Adoptive; D008175:Lung Neoplasms / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000276:immunology*; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment / Q000276:immunology; D000093542:Gemcitabine
chemical_list: D007166:Immunosuppressive Agents; D003841:Deoxycytidine; D000093542:Gemcitabine